Intrinsic and acquired drug resistance by medically relevant microorganisms poses a grave threat to human health and has enormous economic consequences. Fungi are a prominent cause of hospital-acquired infections that are becoming increasingly difficult to control (Pfaller et al., Clin. Microbiol. Rev. 2007, 20:133-163). Fungal pathogens present a particular challenge because they are eukaryotes and share many of the same mechanisms that support the growth and survival of the human host cells they infect. The number of drug classes that have distinct targets in fungi is very limited and the usefulness of current antifungal drugs is compromised by either dose-limiting host toxicity or the frequent emergence of high-grade resistance. New, non-cross-reactive targets for therapeutic intervention are urgently needed (Cowen et al., Proc. Natl. Acad. Sci. USA 2009, 106(8):2818-23).
A frequently overlooked issue in the search for new antifungal targets is that fungal pathogens face a diverse array of environmental challenges during the establishment of invasive infection within a host animal (Cowen et al., PLoS Pathog. 2009, 5(8):e1000471). These can include pH, thermal, and osmotic stresses, as well as the need to utilize alternative carbon sources for energy production (Becker et al., Proc. Natl. Acad. Sci. USA 2010, 107(51):22044-9; Robbins et al., Fungal Genet. Biol. 2010, 47(2):81-93). The role of glycolytic versus respiratory metabolism in supporting fungal virulence and drug-resistance remains unresolved, due in large part to the absence of good tools with which to tackle the question (Brun et al., J. Antimicrob. Chemother. 2005, 56:307-314; Cheng et al., Cell Microbiol. 2007, 9:492-501).